tbuckley/cabot-search huggingface dataset:
Abstract 3932: Targeting cyclin K in pancreatic cancer
Authors: Yi Xiao, Jixin Dong, Yuanhong Chen
Journal: Cancer Research (2023)

Abstract This study focuses on investigating the role of Cyclin K in pancreatic cancer growth and chemotherapeutic sensitivity, aiming to provide pre-clinical evidence for Cyclin K-targeted therapy in pancreatic cancer. Unlike other well-known cyclins, Cyclin K is largely understudied in cancers. Data extracted from the TCGA database indicated that Cyclin K was overexpressed in pancreatic ductal adenocarcinoma (PDAC) and associated with reduced overall survival. Consistently, western blotting showed that Cyclin K was abundantly expressed in human and mouse PDAC cell lines. By using a Tet-On inducible system, we established Cyclin K-depleted and Cyclin K-overexpressed cell lines to evaluate the function of Cyclin K in pancreatic cancer. The proliferation assay showed that Cyclin K depletion led to retarded PDAC cell proliferation, whereas Cyclin K overexpression boosted cell growth. We further confirmed that Cyclin K was required for pancreatic cancer growth in vivo. In addition, cell cycle analysis showed that Cyclin K deficiency resulted in G1-S arrest, while Cyclin K overexpression promoted G1-S progression. By using an RT2 cell cycler array, we identified CDC20 as an important target of Cyclin K that mediated Cyclin K-induced PDAC cell proliferation. To investigate the influence of Cyclin K on chemo-sensitivity, we treated the PDAC cell lines with two newly synthesized Cyclin K molecular glue degraders (HQ461 and NCT02). We found that these degraders specifically ablated Cyclin K and its cognate kinase CDK12 in a very efficient manner. Importantly, we demonstrated that Cyclin K abrogation, either by Cyclin K degrader or Cyclin K knockdown, rendered PDAC cells more sensitive to GemTaxol (gemcitabine plus Taxol) treatment and PARP inhibitors (olaparib or niraparib), as indicated by increased cleavage of PARP or caspase 3. Together, our current results suggest: 1. Cyclin K promotes cell proliferation and G1-S transition in pancreatic cancer; 2. CDC20 mediates the function of Cyclin K on pancreatic cancer cell proliferation; 3. Cyclin K depletion synergizes with GemTaxol or PARP inhibitor in pancreatic cancer treatment. Our study revealed for the first time that Cyclin K plays an essential role in pancreatic cancer growth and chemo-sensitivity, and targeting Cyclin K may offer a great therapeutic avenue for pancreatic cancer patients. Citation Format: Yi Xiao, Jixin Dong, Yuanhong Chen. Targeting cyclin K in pancreatic cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3932.
Abstract 1600: Phase I trial of intravenous mistletoe extract in advanced cancer
Authors: Channing J. Paller, Lin Wang, Wei Fu, Rajedra Kumar, Jennifer Durham, Nilofer Azad, Daniel Laheru, Ilene Browner, Sushant Kachhap, Kavya Boyapati, Thomas Odeny, Deborah Armstrong, Christian Meyer, Stephanie Gaillard, Julie Brahmer, Ivelisse Page, Hao Wang, Luis A. Diaz
Journal: Cancer Research (2023)

Abstract Purpose: Mistletoe extract is widely used in cancer patients to support therapy and to improve quality of life (QoL). However, its use is controversial due to suboptimal trials and a lack of data supporting its intravenous administration. Patients and Methods: This phase I trial of intravenous Mistletoe (Helixor M) aimed to determine the recommended phase 2 dosing and to evaluate safety. Solid tumor patients progressing on at least one line of chemotherapy received escalating doses of Helixor M three times a week. Assessments were also made of tumor marker kinetics and QoL. Results: Twenty-one patients were recruited. The median follow-up duration was 15.3 weeks. The maximum tolerated dose was 600mg. Treatment-related adverse events (AEs) occurred in 13 patients (61.9%), with the most common being fatigue (28.6%), nausea (9.5%), and chills (9.5%). Grade 3+ treatment-related AEs were noted in three patients (14.8%). Stable disease was observed in five patients who had 1-6 prior therapies. Reductions in baseline target lesions were observed in three patients who had 2-6 prior therapies. Objective responses were not observed. The disease control rate (percentage of complete/partial response and stable disease) was 23.8%. The median stable disease was 15 weeks. Serum cancer antigen-125 or carcinoembryonic antigen showed a slower rate of increase at higher dose levels. The median QoL by FACT-G increased from 79.7 at week 1 to 93 at week 4. Conclusions: Intravenous mistletoe demonstrated manageable toxicities with disease control and improved QoL in a heavily pretreated solid tumor population. Future phase II trials are warranted. Citation Format: Channing J. Paller, Lin Wang, Wei Fu, Rajedra Kumar, Jennifer Durham, Nilofer Azad, Daniel Laheru, Ilene Browner, Sushant Kachhap, Kavya Boyapati, Thomas Odeny, Deborah Armstrong, Christian Meyer, Stephanie Gaillard, Julie Brahmer, Ivelisse Page, Hao Wang, Luis A. Diaz. Phase I trial of intravenous mistletoe extract in advanced cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1600.
Abstract 2556: Phosphatase nanozyme combination with kinase inhibitor for decreasing prostate cancer cell viability
Authors: Arailym Myrzagaliyeva, Guldan Nazarbek, Sandugash Myrzagali, Amr Amin, Yingqiu Xie
Journal: Cancer Research (2023)

Abstract Background: Phosphatase has been well studied in anti-cancer research. The dietary amino acid cysteine plays essential roles in protein structure by disulfide bonds, metal ion binding, detoxification, and many metabolic functions. Cysteine has been shown in inducing human bladder cancer cells apoptosis. However, the cysteine mediated nanoparticles enzyme (nanozyme) activity and their function, signaling pathways are yet unknown. We aim to test whether the cysteine mediated nanoparticles nanozyme activity of phosphatase could enhance targeting of kinases. Methods: Fresh L-cysteine were applied for synthesis of less than 200 nm sized nanozyme. The phosphatase enzyme activity was measured using NBT/BCIP substrate. Scanning electron microscopy, transmission electron microscopy were used for nanoparticle analysis. Cell viability was measured by crystal violet staining of cells. Results: L-cysteine at 0.1mg/mL combined with MET inhibitor (1µm or 5µm) showed the better effect of enhanced efficacy and decreased the viability of prostate cancer cells compared to inhibitor alone or cysteine. Combination did not affect the phosphatase activity of cysteine nanozyme. Conclusion: L-cysteine may be applied to be combined with kinase inhibitors in drug delivery for increased efficacy. Citation Format: Arailym Myrzagaliyeva, Guldan Nazarbek, Sandugash Myrzagali, Amr Amin, Yingqiu Xie. Phosphatase nanozyme combination with kinase inhibitor for decreasing prostate cancer cell viability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2556.
Abstract 5337: Design, synthesis and evaluation of dual-targeted mEGFR and AURK inhibitors as anticancer agents
Authors: Dayna Gesinski, Sonali Kurup
Journal: Cancer Research (2023)

Abstract Mutant epidermal growth factor receptor (mEGFR) inhibitors constitute the recommended therapy for mEGFR-positive cancers. However, resistance has developed to mEGFR inhibitors due to newer mutations within the enzyme pocket and redundant signaling pathways that bypass mEGFR inhibition. Recent studies have shown that resistance to mEGFR inhibitors could be overcome if given in combination with aurora kinase (AURK) inhibitors. Dual EGFR/AURK kinase inhibitors provide a novel approach to overcome resistance to EGFR inhibitors. In a previous study, Kurup et al. identified 1 as a nanomolar mEGFR inhibitor. Using a structure-based design approach, novel analogs of 1 that incorporated varied sidechains for dual mEGFR and AURK inhibition were designed. The synthesis of the target compounds involved microwave-assisted, copper and palladium catalyzed coupling reactions. This study led to the identification of dual-targeted mEGFR/AURKA and mEGFR/AURKB inhibitors, and compounds with sub-micromolar cellular potencies. The design, synthesis, kinase inhibitory activities and anticancer effects of these novel analogs will be presented. Structure-activity relationships for mEGFR, AURKA and AURKB inhibition will be defined. Citation Format: Dayna Gesinski, Sonali Kurup. Design, synthesis and evaluation of dual-targeted mEGFR and AURK inhibitors as anticancer agents. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5337.
Abstract 2552: A novel RIP1-mediated canonical WNT signaling pathway promoting colorectal cancer metastasis
Authors: Jong Kuk Park, A-Ram Kang, Jin-Hee Kwon
Journal: Cancer Research (2023)

Abstract RIP1 (receptor interacting protein kinase 1) is an important component of TNF-α signaling that contributes to various pathological effects. We herein reveal new potential roles of RIP1 in controlling WNT/β-catenin canonical signaling to enhance metastasis of colorectal cancer (CRC). Firstly, we show that WNT3A treatment sequentially increases the expression levels of RIP1 and β-catenin. Immunohistochemical analyses of human CRC tissue arrays consisting of normal, primary cancer, and metastatic cancer indicate that elevated RIP1 expression might be related to β-catenin expression, carcinogenesis, and metastasis. Intravenous injection of RIP1 over-expressed CRC cells to mice demonstrates that RIP1 may promote metastasis. Immunoprecipitation (IP) results indicate that WNT3A treatment induces direct binding between RIP1 and β-catenin, and that this stabilizes the β-catenin protein in a manner that depends on the regulation of RIP1 ubiquitination via down-regulation of the E3 ligase, cIAP1/2. Elimination of cIAP1/2 expression and inhibition of its ubiquitinase activity enhances WNT3A-induced RIP1 and β-catenin protein expression and binding, and this stimulates endothelial-mesenchymal transition (EMT) induction to enhance the migration/invasion of CRC cells in vitro. The results of an in vitro binding assay and IP of exogenous RIP1-containing CRC cells additionally verify the direct binding of RIP1 and β-catenin. Finally, RIP1 expression can destroy the β-catenin-β-TrCP complex. Taken together, these results suggest a novel EMT-enhancing role of RIP1 in the WNT pathway and suggest a new canonical WNT3A-RIP1-β-catenin pathway that contributes to CRC malignancy by promoting EMT. Citation Format: Jong Kuk Park, A-Ram Kang, Jin-Hee Kwon. A novel RIP1-mediated canonical WNT signaling pathway promoting colorectal cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2552.
Abstract 5342: Assessment of polyphenolic secondary metabolites and small molecules against the xenobiotic metabolic and cell cycle regulatory proteins in prostate cancer
Authors: Sumit Sheoran, Swati Arora, Tanmay Basu, Naidu Subbarao, Atul Kumar Upadhyay, Sugunakar Vuree
Journal: Cancer Research (2023)

Abstract Background: Prostate cancer (PCa) is the second most frequent kind of cancer in males globally after Lung Cancer. In clinical practice, medicines that act as antagonists/partial agonists of hormone receptors against prostate tissue are employed in PCa treatment. Cyproterone acetate, Flutamide, and Bicalutamide are prominent medications that induce acute and long-term toxicity and create drug resistance in patients and remission. We concentrated on flavonoids since they are non-cytotoxic and have substantial showing inhibitory action. Methodology: We selected 560 flavonoids and small compounds along with 3 targets from the extensive literature review. Three-dimensional (3D) structures of selected proteins were obtained from Protein Data Bank, docked with 560 flavonoids and small molecules 3D structures, obtained from PubChem and CHEMBL database using Gold Docking Software. ADME characteristics were used to determine their bioactivities in the human body and drug-like investigations by using SwissADME and Zinc database, while Lipinski's rule of five was used to evaluate the flavonoids' anti-prostate cancer efficacy. Additionally, we have performed molecular simulation at 100ns and furthermore, we will perform cytotoxicity analysis. Results: Diosmetin (58.72), Lapatinib Ditosylate (121.61), and Estramustine Phosphate Sodium (143.38) has the highest binding affinity for CDKN2 (4EK3), CYP17A1(3RUK), and CYP19A1(3S79), respectively, and are stable throughout 100ns simulation studies. At present, we are working on cytotoxicity studies on PC3 cell lines. As per the literature review by Ansar et al. 2022 quercetin and thymoquinone induce cytotoxicity in breast, lung, and prostate cancer cells effectively; MCF-7 cells were the most sensitive cells to quercetin with an IC50 value of 50 μM and PC3 cells were more sensitive to thymoquinone with an IC50 value of 20 μM. Conclusion: As a result of our findings, these four Flavonoids may be viable candidates for additional research into PCa prevention or management.Keywords: Diosmetin, Lapatinib Ditosylatye, Prostate cancer, In-silico, Simulation Citation Format: Sumit Sheoran, Swati Arora, Tanmay Basu, Naidu Subbarao, Atul Kumar Upadhyay, Sugunakar Vuree. Assessment of polyphenolic secondary metabolites and small molecules against the xenobiotic metabolic and cell cycle regulatory proteins in prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5342.
Abstract 2790: Preclinical studies of ZG19018, a novel irreversible covalent inhibitor of KRAS G12C, for the treatment of advanced non-small cell lung cancer and other solid tumors
Authors: Bing Zhu, Dawei Cui, Ruifeng Liu, Weidong Feng, Zelin Sheng, Binhua Lv
Journal: Cancer Research (2023)

Abstract Growing evidences of covalent irreversible inhibitors in clinical treatments of solid tumors with KRAS G12C mutation have recently emerged after FDA-approved AMG510 (Sotorasib) for NSCLC chemotherapies. ZG19018 is an irreversible KRAS G12C inhibitor with novel structure that shows promising preclinical results for in vitro molecular and biological studies and in vivo G12C-mutated cancer models and safety studies in animals. For instance, ZG19018 rapidly and selectively forms covalent bonds with G12C-GDP, which accounts for lock-in KRAS protein as the inactive GDP-bound state but inhibits the activation of numerous downstream signaling pathways like RAF/MEK on ERK phosphorylation. ZG19018 showed highly inhibition of a 3D growth panel for human cancer cell lines harboring the KRAS G12C mutation, e.g. H358 (NSCLCs), MIA PaCa-2 (pancreatic) and SW837 (colorectal), etc. For pharmacodynamics, a battery of in vitro and in vivo ADME/DMPK studies indicated a high plasma protein binding (&amp;gt;99.6%) of ZG19018 with over 40% bioavailability in rat and dog via oral administration for the adequate drug levels in various tissues including lung, crossing BBB to reach brain, and accumulation in tumors. For in vivo anti-tumor efficacy, ZG19018 exhibited significant dose-dependent inhibition of tumor growth of G12C-driven subcutaneous models in nude mouse like H358 NSCLC cells but induced further tumor regression in pancreatic cancer MIA PaCa-2 xenograft. ZG19018 also showed an enhanced anti-tumor activities as combined with chemo-reagent Donafinib, a broad tyrosine kinase inhibitor blocking RAF/MEK/ERK signaling pathways of tumor cells, in the same H358 xenograft model. The general toxicology studies in rat under 28 days repeated oral administration (q.d.) showed NOAEL and STD10 values at 75 and 150 mg/kg/day, respectively. The safety pharmacological studies showed no notable effects of ZG19018 on the cardiovascular, respiratory and CNS systems. The genotoxic potential studies indicated ZG19018 without mutagenesis. Collectively, ZG19018 is now in phase I/II clinical trials for the treatments of solid tumors with KRAS G12C mutation in China. Citation Format: Bing Zhu, Dawei Cui, Ruifeng Liu, Weidong Feng, Zelin Sheng, Binhua Lv. Preclinical studies of ZG19018, a novel irreversible covalent inhibitor of KRAS G12C, for the treatment of advanced non-small cell lung cancer and other solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2790.
Abstract 1987: Delivery of potent cytotoxic camptothecin derivatives to tumors by OncoFAP-based small molecule-drug conjugates
Authors: Matilde Bocci, Samuele Cazzamalli, Dario Neri, Andrea Galbiati
Journal: Cancer Research (2023)

Abstract Small Molecule-Drug Conjugates (SMDCs) are anti-cancer pro-drugs composed by a tumor-targeting small organic ligand, a linker structure and a potent cytotoxic payload. OncoFAP is an ultra-high affinity ligand of Fibroblast Activation Protein (FAP), a stromal protein overexpressed in multiple types of solid human malignancies. Nuclear medicine studies validated the applicability of the OncoFAP technology for tumor-targeting applications in a wide variety of tumor types. We have recently reported the development of SMDC products in which OncoFAP is used to deliver Monomethyl Auristatin E (MMAE) to tumors, exploiting linkers that are selectively cleaved by FAP. Here we describe the generation and in vivo characterization of novel OncoFAP-based SMDC products bearing potent camptothecin derivatives acting as topoisomerase I inhibitors. Those drug payloads have been already included in approved ADC products (EnhertuTM and TrodelvyTM). The FAP-cleavable linker technology was directly compared against linker strategies used for approved ADCs. Therapy results in preclinical xenograft models of solid tumors revealed that SMDC products activated by FAP show superior anti-cancer activity and deserve industrial development for the treatment of various human solid tumors. Citation Format: Matilde Bocci, Samuele Cazzamalli, Dario Neri, Andrea Galbiati. Delivery of potent cytotoxic camptothecin derivatives to tumors by OncoFAP-based small molecule-drug conjugates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1987.
Abstract 2060: The exploratory analysis of dysregulated transcription factor FOXC1 in pan-cancer
Authors: Alanna Brown, Zexun Wu, Huan Cao, Sara M. Falzarano, Sarah G. Buxbaum, Suhn K. Rhie
Journal: Cancer Research (2023)

Abstract FOXC1 is a transcription factor that is reported to play a key role in the development of cancer. For example, we showed that epigenetic dysregulation of FOXC1 is associated with meningioma progression. Moreover, we reported that FOXC1 is overexpressed in drug-resistant bladder cancer cells. To further characterize the molecular mechanisms of FOXC1 in carcinogenesis of different cancer types, we analyzed DNA-seq and RNA-seq datasets of over 30 cancer types generated from The Cancer Genome Atlas (TCGA) and Oncology Research Information Exchange network (ORIEN) consortia, using cBioportal. cBioportal is a tool that is used to visualize and analyze large-scale cancer genomic data. When we analyzed whole exome sequencing and DNA array datasets to search genetic alterations such as mutation, amplification, and deletion events that occur in the FOXC1 gene, we revealed that over 10 cancer types have genetic alterations. By analyzing RNA sequencing datasets through the cBioportal, we found that more than 10 cancer types have overexpression of FOXC1. Unlike TCGA, ORIEN has generated whole exome sequencing and RNA sequencing datasets from cancer patients who are treated. We are currently in the process of analyzing ORIEN data to determine FOXC1 alterations and its association with drug resistance in different cancer types. Moreover, we are evaluating the relationship between FOXC1 dysregulation and cancer patient survival. Overall, this analysis will denote the key role that FOXC1 plays in different cancer types and supply valuable knowledge for drug resistance. Citation Format: Alanna Brown, Zexun Wu, Huan Cao, Sara M. Falzarano, Sarah G. Buxbaum, Suhn K. Rhie. The exploratory analysis of dysregulated transcription factor FOXC1 in pan-cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2060.
Abstract 1396: The HOX family gene signature predicts prognosis and indicates immune infiltrates in pediatric gliomas
Authors: Qianhao Zhao, Junyan Su
Journal: Cancer Research (2023)

Abstract Background: Pediatric gliomas (PGs) are highly aggressive and predominantly occur in young children. Homeobox (HOX) family genes are transcription factors that play a crucial role in anterior-posterior body axis patterning during embryonic development. This study aimed to propose a novel HOX-related signature of PGs to predict patients’ prognosis and immune infiltrate characteristics. Methods: Multiple levels of data (whole-exome sequencing, mRNA-sequencing, and single-cell RNA-sequencing) of 571 PGs obtained from publicly available databases were utilized to reveal the relationship among abnormal expression of HOX family genes, prognosis, tumor immune infiltration, clinical features, and genomic features in PGs. A total of 39 HOX family genes were utilized to identify heterogeneous subtypes using consensus clustering. Then a random forest-supervised classification algorithm and a nearest shrunken centroid algorithm were performed to develop a prognostic signature in the training group and validated in two test groups and an independent cohort. Results: Here, we first identified 39 HOX family genes significantly differentially expressed in PGs compared to adjacent normal tissues. Then the individuals with PGs were then divided into two heterogeneous clusters (cluster 1 and cluster 2) based on HOX family gene expression profiles. Cluster 2 showed higher total mutation counts, lower immune infiltration, and worse prognosis than cluster 1. Finally, we constructed a four-hub-HOX gene signature (including HOXA2, HOXA6, HOXC5, and HOXC6) based on the cluster for subtype prediction applying a random forest supervised classification algorithm and a nearest shrunken centroid algorithm. The signature was revealed to be an independent prognostic factor for patients with PGs by multivariable Cox regression analysis. Conclusion: Our results provide a novel method for the prognosis classification of PGs. The findings also suggest that the four-hub-HOX gene signature is a new biomarker for the prognosis of patients with PGs, allowing for more accurate survival prediction. Citation Format: Qianhao Zhao, Junyan Su. The HOX family gene signature predicts prognosis and indicates immune infiltrates in pediatric gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1396.